Clinical Activities and Training

Division Photo

Row 1: B Lampkin

Row 2: P Malik, K Kalinyak, T Kalfa

Row 3: C Quinn, E Mullins, C Tarango

Row 4: J Palumbo

Division Highlights

Punam Malik, MD & Jay Degen, PhD

A scientific collaboration between Drs. Punam Malik and Jay Degen is revealing a novel role for hemostatic system components in the pathogenesis of organ dysfunction related to sickle cell disease (SCD). Using mouse models of SCD and novel genetic tools for altering key coagulation system components in vivo, Drs. Malik and Degen directly established that interventions at the level of hemostatic factors could significantly ameliorate SCD-related organ pathologies and dramatically improve long-term survival. Their initial findings were the foundation for a newly-funded, multi-investigator grant from the National Heart, Lung and Blood Institute.

Theodosia Kalfa, MD

Dr. Theodosia Kalfa’s laboratory has developed a state-of-the-art method to analyze terminal erythropoiesis using multiparameter high-speed cell imaging in flow. They demonstrated in a highlighted publication in Blood that erythroblast enucleation is a more complex process than previously thought, requiring a multistep action of tubulin and filamentous actin, as well as lipid raft formation coordinated by Rac GTPases. This study creates the basis for further research on terminal erythroid maturation with the potential to improve the efficiency of red blood cell production in vitro.

Thrombosis Program

Our thrombosis program has collaborated with Interventional Radiology in expanding the use of site-directed mechanical and pharmacologic thrombolysis in the treatment of blood clots in children and adolescents. The prompt restoration of venous blood flow by clot lysis procedures will significantly reduce the long-term consequences of thrombosis for our patients. Only a few pediatric centers nationally offer this therapeutic option. As such, we are increasing our referrals from other pediatric thrombosis centers for the procedure.

Charles T. Quinn, MD, MS

The American Society of Hematology (ASH) recognized Dr. Charles Quinn’s work in sickle cell disease by choosing him as a National and International Program Co-chair and Speaker for the Highlights of ASH program in North America, Latin America and Asia.

Sickle Cell Center

The Sickle Cell Center has been awarded several national and regional grants that focus on improving outcomes for patients with SCD and related hemoglobinopathies. Dr. Lori Crosby was awarded over 2 million dollars in grant funding from the National Heart, Lung and Blood Institute as part of a collaboration between the Divisions of Hematology and Behavioral Medicine to study mechanisms to improve the crucial and complicated transition of sickle cell patients from the pediatric to the adult setting. Ms. Lisa Shook has been named the Program Director/Health Educator of the Ohio Department of Health Regional Sickle Cell Services Program, Bureau for Children with Medical Handicaps. The purpose of this program is promoting the early identification of children and adults with SCD and related hemoglobinopathies and facilitating their integration into systems of care that are accessible, continuous, comprehensive, family-centered, coordinated and culturally sensitive.

For this work, we developed a novel analysis protocol using multispectral high-speed cell imaging in flow to visualize and investigate the evanescent event of erythroblast enucleation, in a high enough number to produce reliable and statistically evaluable results. Thus we demonstrated that erythroblast enucleation is a more complex and multistep process than previously thought, resembling asymmetric cytokinesis: it requires establishment of cell polarity through microtubule function, followed by formation of a contractile actomyosin ring, and coalescence of lipid rafts between reticulocyte and pyrenocyte. We showed that Rac GTPases organize actin in the actomyosin ring and aggregate lipid rafts in the furrow between nascent reticulocyte and pyrenocyte during enucleation. Understanding of the mechanism of erythroblast enucleation is critical in order to reveal targets for in vivo therapeutic intervention for anemias due to terminal erythroid maturation defects as well as for improving the efficiency of red blood cell production in vitro.

Sickle cell anemia patients are at significant risk for the development of strokes, silent cerebral infarcts (SCI) and cognitive impairment. SCIs are the most common form of neurologic injury among children with sickle cell anemia occurring in at least 27% before 6 years of life and 37% by 14 years of life. This cross-sectional study examined potential risk factors in a well characterized group of children with no history of any neurological symptoms and whose MRIs were performed and read by the Neuroradiology Committee using a protocol detailed in this report. This study showed that low baseline hemoglobin concentrations and relative high systolic blood pressures are risk factors for the development of SCI. While this study did not examine treatments for preventing SCI, it does provide the basis for further research that might focus on increasing baseline hemoglobin in these young children and/or attenuate factors that contribute to the development of the relative high systolic blood pressures. Decreasing the occurrence of SCI in children with sickle cell anemia would likely result in improved outcomes with regard to decreasing the neurocognitive effects of this disease.

Renal complications affect nearly 30-50% of adults with sickle cell anemia (SCA), causing significant morbidity and mortality. Standard renal function tests like serum creatinine and glomerular filtration rate become abnormal in this disease only when renal damage has become extensive and largely irreversible. Moreover, not all patients develop sickle nephropathy (SN). Therefore, noninvasive biomarkers that predict early onset of SN are necessary.

Our study identifies potential biomarkers for SN, and suggests longitudinal validation of these biomarkers for early detection of SN, so that therapeutic interventions can be applied before renal damage becomes irreversible.

These studies demonstrated, for the first time, that thrombomodulin, a key endothelial cell-associated regulator of thrombin activity and generation, is an important determinant of metastasis. These studies add a fundamental new dimension to the general understanding of hemostatic factors and cancer by directly establishing that endothelial cell-associated regulators of hemostatic function are major determinants of the malignant phenotype. Furthermore, these studies suggest that therapeutic strategies aimed at preserving or augmenting thrombomodulin-mediated regulation of thrombin could limit tumor dissemination.

Thalassemia is a common blood disease that affects many organ systems, including the heart and lungs. This manuscript describes an NIH-funded, multi-center clinical investigation of the prevalence and predictors of an elevated tricuspid regurgitant jet velocity (TRJV), a marker for pulmonary hypertension, in children and adults with thalassemia intermedia and major. This study showed that an abnormally elevated TRJV was common in thalassemia—occurring in ⅓ of patients—and was associated with older age, splenectomy, hepatitis C infection, and smoking. These findings permit the better identification of individuals at risk for pulmonary hypertension, and highlight the role of splenectomy as an antecedent of pulmonary hypertension.

Division Collaboration

Human Genetics » Mehdi Keddache, PhD and Kejian Zhang, MD

Development of a high-throughput gene chip for the diagnosis of known and discovery of new genetic mutations causing hemolytic anemia due to erythrocyte cytoskeleton disorders, e.g. spherocytosis, elliptocytosis. (T Kalfa, MD, PhD.)

Nephrology »

Development of special assays and genetic tests that will aid in the diagnosis and management of children with atypical hemolytic syndrome (aHUS), an acute illness with high morbidity and mortality. (R Gruppo, MD)

Cardiology » David Nelson, MD, PhD and Dave Cooper, MD

Forming an anticoagulation team for the cardiac intensive care unit. (C Tarango, MD)

Improving Sickle Cell Disease outcomes. Working on a standardized approach to be sure that every patient over the age of 5 years has a home pain management plan and that this plan is outlined clearly in the electronic medical record. Working on a standardized pain management approach in the emergency department. Working on closely monitoring the timing of patients getting their first Transcranial Doppler Study to identify patients at the highest risk of having a stroke. (K Kalinyak, MD)